Yersinia pestis is an incidental human pathogen that is the causative agent of plague. Historically plague has been a significant source of human morbidity and mortality. In areas where plague is endemic in rodent populations humans are still at significant risk. Plague may re-emerge as a significant danger to human health due to the recent identification of multi-drug resistant strains of Y. pestis and the possibility that Y. pestis may be used as an agent of biological terrorism. Although plague has been a major health problem for more than 1500 years, relatively nothing is known about the pathogenesis of Y. pestis infection. In particular, detailed molecular data on the host response to Y. pestis infection is lacking. This data is crucial for the development of new treatments and may significantly improve vaccine strategies. Using the mouse model of Y. enterocolitica infection combined with microarray analysis of infected tissues we have gained significant insight into the host response to the enteropathogenic Yersiniae. These studies have improved our understanding of the molecular basis of the host response to Y. enterocolitica and should serve as a template for an analysis of the host response to Y. pestis. Based on our previous investigations we hypothesize that: Y. pestis infection induces the expression of genes encoding immunomodulatory proteins (cytokines, chemokines, proteases, and immune effectors) and the expression of these proteins dictates the outcome of the infection. To test these hypotheses we propose: 1) A comprehensive analysis of host gene expression to Y. pestis infection 2) Analysis of the effect of defined host deficiencies on the immune response to Y. pestis infection in vivo. We will utilize microarray analysis of tissues from Y. pestis infected mice including defined (cytokines) host mutants to study the host response to plague. Additionally the roles of cytokines (TARC, TGF-beta, TNF-alpha, IL-13, IL-6, IL-10) will be examined using the mouse model of infection. These studies will improve our understanding of the host immune response to Y. pestis infection. [unreadable] [unreadable] [unreadable] [unreadable]